It is well known that the lymphatic tissues are involved in most pathological processes. They are highly responsive even to minor disturbances in the surrounding tissues and represent a sensitive indicator of disease. The status of lymph nodes is especially important in cases of severe disease, such as metastatic cancer, where detection and accurate lymph node staging are essential to successful therapy. While histopathology is in many cases the most accurate method of lymph node assessment, this approach requires a surgical procedure and is limited to regional anatomic sites. Current techniques in medical imaging often use size criteria to assess tumor involvement of a lymph node. However, size is an imperfect indicator since normal-sized nodes may contain cancer while enlarged nodes may be cancer-free. Therefore, diagnostic preparations that selectively highlight the details of lymph node structure and function could improve both the sensitivity and specificity of major modern diagnostic methods, such as nuclear medicine, magnetic resonance imaging, and x-ray computed tomography. The efficacy of therapy, in turn, may be dramatically improved by increasing the local concentration of a drug in the injured tissue. Agents that can reach all lymph nodes after a single intravascular injection are preferable because of the large number of lymph nodes in the human body and difficult access to most of them.
The structure of the lymphatic system allows drug delivery to the lymph nodes by drainage of an interstitially localized preparation through the lymphatic vessels. This route has been adopted for the lymphography and imaging of the peripheral lymph nodes and has recently been suggested for administration of therapeutic preparations, such as anticancer agents immobilized on dextran molecules or on colloidal carbon particles.
Previously, preparations, including carbohydrates and their derivatives, have been delivered to the lymph nodes by local (interstitial or intralymphatic) administration. The behavior of locally administered preparations in the lymphatic system depends on the type of preparation. For example, while colloids are often taken up from the lymph by the lymph node cells, some polymeric preparations, such as dextran, can pass through lymph nodes via the lymphatic sinuses without significant uptake. After intravascular administration, a major fraction of many conventional preparations are taken up by the liver and spleen rather than by lymphatic tissues. The polymeric preparations show some uptake by the lymphatic system, but the lack of their accumulation in the lymph node tissue renders them less desirable as targeted diagnostic or therapeutic substances. These preparations, therefore, are likely useful for investigation of the lymph nodes located in easily accessible surface areas of the organism, but not for lymph nodes located in less accessible areas.
Despite the absence of significant accumulation in the lymphatic tissues after intravascular administration, previous preparations were used in biological models for lymph node investigation. Metalloporphyrins have been used for the delivery of a radionuclide to the lymph nodes but the total amount of the isotope delivered to the lymph nodes did not usually exceed about 1%. It has also been shown in Weissleder, R. et al., "Ultrasmall Supermagnetic Iron Oxide: Pharmacokinetics and Toxicity", American Journal of Radiology, 1989, Vol. 152, pp. 167-73, that a minor fraction (about 3.6% of the dose/gram of tissue) of previous preparations of ultra-small iron oxide particles appeared in the lymphatic tissues after intravascular injection but the majority of these particles are found in the liver and spleen. Only minimal amounts of the particles were detectable in lymph nodes and other tissues. Iron oxide particles may be used for magnetic resonance in imaging as discussed in U.S. Pat. Nos. 4,770,183 and 4,827,945, and for producing contrast images of tissue including lymph node tissue.
Macromolecular drug complexes have been intensively studied as prototypes of parenteral diagnostic and therapeutic preparations. They typically consist of a carrier (e.g., polymeric molecules, vesicles, and microparticles) and agent molecules attached or incorporated therewith. The role of a carrier is to alter the biodistribution of an agent, to increase its concentration in a desirable target tissue, and to decrease its concentration in non-target sites thereby suppressing side effects. To provide accumulation of a drug complex in a target site, molecules possessing a high affinity to target tissue are often used as components of a carrier. Antibodies or their fragments, and receptor ligands (e.g., hormones or their analogues) are common examples of high affinity molecules used in targeted drugs.
Drug targeting, as a pharmacokinetic concept, is generally based on the postulate that the agent should not significantly affect the pharmacokinetics or the biodistribution of the carrier. However, certain agents are able to interact with plasma or cell surface components, and can cause a dramatic difference between the biodistribution of the carrier and the drug complex.
Once the drug complex has accumulated in the targeted tissue, the behavior of the agent depends on the method of its attachment or incorporation with the carrier.
The appearance of minor fractions of intravascularly administered substances in the lymph nodes has been reported for a diverse group of polymers and colloids (e.g., polyvinyl alcohol, iron dextran, dextran, liposomes). These substances were seldom found in the lymph node cells, other than in the macrophages or mast cells and their uptake by the lymph nodes was insignificant. Similar cells are responsible for the uptake of these substances in the liver, spleen, bone marrow, kidney and other organs.